Stage IB Lung Non-Small Cell Carcinoma AJCC v7, Stage IIA Lung Non-Small Cell Carcinoma AJCC v7, Stage IIB Lung Non-Small Cell Carcinoma AJCC v7, Stage IIIA Lung Non-Small Cell Cancer AJCC v7
Conditions
Brief summary
This randomized phase III trial studies chemotherapy and bevacizumab to see how well they work compared to chemotherapy alone in treating patients with stage IB, stage II, or stage IIIA non-small cell lung cancer that was removed by surgery. Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving more than one drug (combination chemotherapy) may kill more tumor cells. Monoclonal antibodies, such as bevacizumab, may interfere with the ability of tumor cells to grow and spread. Bevacizumab also may stop the growth of non-small cell lung cancer by blocking the growth of new blood vessels necessary for tumor growth. It is not yet known whether chemotherapy is more effective with or without bevacizumab in treating non-small cell lung cancer.
Detailed description
PRIMARY OBJECTIVES: I. To evaluate overall survival with chemotherapy with or without bevacizumab used in the adjuvant setting in patients with resected stage IB (\>= 4 cm) - IIIA non-small cell lung cancer (NSCLC). SECONDARY OBJECTIVES: I. To evaluate disease-free survival and toxicity with chemotherapy with or without bevacizumab used in the adjuvant setting in patients with resected stage IB (\>= 4 cm) - IIIA NSCLC. CORRELATIVE OBJECTIVES: I. To perform analyses of tissue and blood to establish factors that predict clinical outcome in patients receiving chemotherapy, with or without bevacizumab, for resected early stage NSCLC. II. To determine whether smoking status is linked to outcome for patients with resected stage IB (\>= 4 cm) - IIIA NSCLC treated with chemotherapy with or without bevacizumab in the adjuvant setting. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I (adjuvant chemotherapy without bevacizumab): Patients receive 1 of 4 chemotherapy regimens. REGIMEN 1: Patients receive vinorelbine ditartrate intravenously (IV) over 10 minutes on days 1 and 8 and cisplatin IV over 60 minutes on day 1 immediately following vinorelbine ditartrate administration. REGIMEN 2: Patients receive docetaxel IV over 1 hour on day 1 and cisplatin over 1 hour on day 1 immediately following docetaxel administration. REGIMEN 3: Patients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and cisplatin IV over 60 minutes on day 1 immediately following gemcitabine administration. REGIMEN 4 (non-squamous histology only): Patients receive pemetrexed disodium IV over 10 minutes and cisplatin IV over 1 hour on day 1 immediately following pemetrexed disodium administration. In all regimens, treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. ARM II (adjuvant chemotherapy with bevacizumab): Patients receive chemotherapy as in Arm I. Patients also receive bevacizumab IV over 30-90 minutes on day 1. Treatment with bevacizumab repeats every 21 days for up to 1 year. After completion of study treatment, patients are followed up periodically for 10 years.
Interventions
BIOLOGICALBevacizumab
Given IV
DRUGCisplatin
Given IV
DRUGDocetaxel
Given IV
DRUGGemcitabine Hydrochloride
Given IV
OTHERLaboratory Biomarker Analysis
Correlative studies
DRUGPemetrexed Disodium
Given IV
OTHERQuestionnaire Administration
Ancillary studies
DRUGVinorelbine Tartrate
Given IV
Sponsors
National Cancer Institute (NCI)
Cancer and Leukemia Group B
NCIC Clinical Trials Group
North Central Cancer Treatment Group
SWOG Cancer Research Network
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* In order to be eligible for this trial, patients must have undergone complete resection of their non-small cell lung cancer (NSCLC) \[stage IB (\>= 4 cm)\] - \[IIIA (T2-3N0, T1-3N1, T1-3N2\] prior to enrollment; accepted types of resection will consist of lobectomy, sleeve lobectomy, bi-lobectomy or pneumonectomy; resections by segmentectomy or wedge resection will not be accepted; mediastinal lymph node sampling at specified levels is required pre-operatively (mediastinoscopy) or intraoperatively (level 7 and 4 for right sided tumors or level 7 and 5 and/or 6 for left sided tumors) * Patients must be no less than 6 weeks (42 days) and no more than 12 weeks (84 days) post-thoracotomy at the time of randomization and must be adequately recovered from surgery * Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 * Patients must not have received the following: * Prior systemic chemotherapy at any time; methotrexate (MTX) given in low doses for non-malignant conditions with last dose at least 2 weeks prior to date of registration will be allowed; other low dose chemotherapeutics for non-malignant conditions will be considered, but review by the study chair is required * Hormonal cancer therapy or radiation therapy as prior cancer treatment within 5 years of randomization; (prior surgery, biologic therapy, hormonal therapy, or radiation therapy for a malignancy over 5 years prior to enrollment that is now considered cured is acceptable) * Patients must not have any history of cancer within 5 years from randomization, with the exception of in-situ carcinoma of the cervix or completely resected non-melanoma skin cancer * Absolute neutrophil count (ANC) \>= 1500 mm\^3 * Platelets \>= 100,000/mm\^3 * Prothrombin time/international normalized ratio (INR) =\< 1.5 * Or, if patient is on therapeutic anticoagulation, prothrombin time/INR =\< 3.0 * Partial thromboplastin time (PTT) =\< institutional upper limit of normal (ULN) OR, if patient is on therapeutic anticoagulation, PTT must be =\< 1.5 x ULN * Total bilirubin =\< 1.5 mg/dL * Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase \[AST\]) \< 5 x upper limit of normal (ULN) * Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase \[ALT\]) \< 5 x upper limit of normal (ULN) * Serum creatinine =\< 1.5 x institutional upper limit of normal (ULN) * Urine protein should be screened by urine analysis for urine protein creatinine (UPC) ratio; for UPC ratio \> 0.5, 24-hour urine protein must be obtained and the level must be \< 1000 mg (1 g) for patient enrollment * Patients with a known history of myocardial infarction or other evidence of arterial thrombotic disease (angina) will be allowed on study only if they have had no evidence of active disease for at least 12 months prior to randomization * Patients with any history of cerebral vascular accident (CVA) or transient ischemic attack (TIA) will not be allowed on trial * Women must not be pregnant or breast-feeding * All females of childbearing potential must have a blood or urine test within 2 weeks prior to randomization to rule out pregnancy * Both fertile men and women must agree to use adequate contraceptive measures during study treatment and for at least 6 months after completion of bevacizumab * Patients must not have any clinically significant ongoing, active or serious infection, symptomatic or uncontrolled congestive heart failure, symptomatic or uncontrolled cardiac arrhythmia or any other medical condition or psychiatric illness/social situations that would limit compliance with study requirements * Patients must have no history of bleeding diathesis or coagulopathy * All patients must have a documented blood pressure (BP) with systolic =\< 150 and diastolic =\< 90 within 28 days of registration; patients with known hypertension must be on a stable regimen of anti-hypertensive therapy * Patients receiving daily treatment with aspirin or non-steroidal anti-inflammatory agents (NSAIDS) are eligible; treatment with dipyridamole (Persantine), ticlopine (Ticlid), clopidogrel (Plavix) and/or cilostazol (Pletal) is not allowed; patients must have stopped taking any of these agents at least 7 days prior to randomization * Patients must not have serious non-healing wound, ulcer, bone fracture, or have undergone a major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to randomization OR core biopsy within 7 days prior to randomization * Patients must not have a history of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 28 days prior to randomization * Patients must not have any anticipated major surgical procedure(s) during the course of the study * Patients must not have known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies * Patients may be on a stable regimen of therapeutic anticoagulation or may be receiving prophylactic anticoagulation of venous access devices, provided that coagulation studies meet entry criteria above; caution must be exercised for patients requiring anticoagulation, including treatment with low dose heparin or low molecular weight heparin for deep vein thrombosis (DVT) prophylaxis while on study * Patients with ongoing post-operative hemoptysis (defined as bright red blood of 1/2 teaspoon or more) are not eligible; patients with pre-operative hemoptysis that has resolved post-operatively are eligible * Patients who will receive pemetrexed (pemetrexed disodium)/cisplatin therapy must also meet the following criteria: * Patients assigned to pemetrexed/cisplatin therapy must NOT have squamous cell histology * Calculated creatinine clearance must be obtained within 2 weeks of randomization and calculated creatinine clearance (CrCl) must be \>= 45 mL/min using the standard Cockcroft and Gault formula, or the measured glomerular filtration rate (GFR) using the appropriate radiolabeled method (\[51\]chromium-labeled ethylenediaminetetraacetic acid \[51-CrEDTA\] or technetium 99m diethylenetriamine-pentaacetic acid \[Tc99m-DTPA\]) must be used to calculate CrCl
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | From registration to death, up to 10 years | Overall survival (OS) was defined as the time from randomization to death from any cause, and patients who were thought to be alive at the time of final analysis were censored at the last date of contact. The study failed to meet its primary endpoint. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease-free Survival | From registration to death, up to 10 years | Disease-free survival (DFS) was defined as the time from randomization to an event. Events include disease recurrence, new primary of lung cancer, second primaries or death, whichever occurred first; however, it should be noted that patients with new primaries at other non-lung sites should have continued followup for recurrence of the original cancer. Patients that have not had an event reported at analysis were censored at their last date of disease assessment. |
Countries
Canada, Ireland, Peru, South Africa, United States
Contacts
PRINCIPAL_INVESTIGATORHeather A Wakelee
ECOG-ACRIN Cancer Research Group
Participant flow
Recruitment details
Patients were recruited between June 1, 2007 and September 20, 2013 from ECOG-ACRIN, SWOG, RTOG, CALGB, NCCTG, NCIC-CTG, NSABP, ACOSOG, and CTSU sites.
Participants by arm
| Arm | Count |
|---|---|
| Arm I (Chemotherapy) Patients receive one of the following. For all, treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.
REGIMEN 1: Vinorelbine ditartrate 30 mg/m2 IV on days 1 and 8, cisplatin 75 mg/m2 IV over 60 minutes on day 1 REGIMEN 2: Docetaxel 75 mg/m2 IV and cisplastin 75 mg/m2 IV on day 1 REGIMEN 3: Gemcitabine hydrochloride 1200 mg/m2 IV on days 1 and 8, cisplatin 75 mg/m2 IV on day 1 REGIMEN 4 (non-squamous histology only): Pemetrexed disodium 500mg/m2 IV and cisplatin 75 mg/m2 IV on day 1
Cisplatin: Given IV
Docetaxel: Given IV
Gemcitabine Hydrochloride: Given IV
Pemetrexed Disodium: Given IV
Vinorelbine: Given IV | 749 |
| Arm II (Chemotherapy, Bevacizumab) Patients receive chemotherapy as in Arm I. Patients also receive bevacizumab IV over 30-90 minutes on day 1. Treatment with bevacizumab repeats every 21 days for up to 1 year.
Bevacizumab: Given IV
Cisplatin: Given IV
Docetaxel: Given IV
Gemcitabine Hydrochloride: Given IV
Pemetrexed Disodium: Given IV
Vinorelbine: Given IV | 752 |
| Total | 1,501 |
Baseline characteristics
| Characteristic | Arm II (Chemotherapy, Bevacizumab) | Total | Arm I (Chemotherapy) |
|---|---|---|---|
| Age, Continuous | 60.8 years STANDARD_DEVIATION 8.7 | 60.8 years STANDARD_DEVIATION 8.8 | 60.7 years STANDARD_DEVIATION 9 |
| Chemotherapy Cisplatin/Docetaxel | 171 Participants | 343 Participants | 172 Participants |
| Chemotherapy Cisplatin/Gemcitabine | 141 Participants | 283 Participants | 142 Participants |
| Chemotherapy Cisplatin/Pemetrexed | 249 Participants | 497 Participants | 248 Participants |
| Chemotherapy Cisplatin/Vinorelbine | 190 Participants | 377 Participants | 187 Participants |
| Chemotherapy Unknown/Missing | 1 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 29 Participants | 48 Participants | 19 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 688 Participants | 1368 Participants | 680 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 35 Participants | 85 Participants | 50 Participants |
| Histology Adenocarcinoma | 450 Participants | 874 Participants | 424 Participants |
| Histology Bronchioloalveolar carcinoma (BAC) | 5 Participants | 13 Participants | 8 Participants |
| Histology Combined/mixed | 48 Participants | 93 Participants | 45 Participants |
| Histology Large cell | 16 Participants | 38 Participants | 22 Participants |
| Histology Not otherwise specified (NOS) | 16 Participants | 40 Participants | 24 Participants |
| Histology Other | 10 Participants | 20 Participants | 10 Participants |
| Histology Squamous | 206 Participants | 422 Participants | 216 Participants |
| Histology Unknown/missing | 1 Participants | 1 Participants | 0 Participants |
| Performance Status Ambulatory | 310 Participants | 620 Participants | 310 Participants |
| Performance Status Fully active | 440 Participants | 879 Participants | 439 Participants |
| Performance Status Unknown/missing | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 5 Participants | 6 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 16 Participants | 38 Participants | 22 Participants |
| Race (NIH/OMB) Black or African American | 57 Participants | 131 Participants | 74 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 2 Participants | 5 Participants | 3 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 12 Participants | 19 Participants | 7 Participants |
| Race (NIH/OMB) White | 660 Participants | 1302 Participants | 642 Participants |
| Sex: Female, Male Female | 381 Participants | 755 Participants | 374 Participants |
| Sex: Female, Male Male | 371 Participants | 746 Participants | 375 Participants |
| Urine protein | 100.25 mg/dL STANDARD_DEVIATION 32.28 | 97.79 mg/dL STANDARD_DEVIATION 41.86 | 95.26 mg/dL STANDARD_DEVIATION 32.28 |
| Urine protein:creatinine (UPC) ratio | 0.18 ratio STANDARD_DEVIATION 0.92 | 0.25 ratio STANDARD_DEVIATION 2.28 | 0.31 ratio STANDARD_DEVIATION 3.1 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| other Total, other adverse events | 474 / 738 | 509 / 735 |
| serious Total, serious adverse events | 424 / 738 | 563 / 735 |
Outcome results
Primary
Overall Survival
Overall survival (OS) was defined as the time from randomization to death from any cause, and patients who were thought to be alive at the time of final analysis were censored at the last date of contact. The study failed to meet its primary endpoint.
Time frame: From registration to death, up to 10 years
Population: All enrolled patients
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I (Chemotherapy) | Overall Survival | NA months |
| Arm II (Chemotherapy, Bevacizumab) | Overall Survival | 85.8 months |
p-value: 0.995% CI: [0.82, 1.19]Regression, Cox
Secondary
Disease-free Survival
Disease-free survival (DFS) was defined as the time from randomization to an event. Events include disease recurrence, new primary of lung cancer, second primaries or death, whichever occurred first; however, it should be noted that patients with new primaries at other non-lung sites should have continued followup for recurrence of the original cancer. Patients that have not had an event reported at analysis were censored at their last date of disease assessment.
Time frame: From registration to death, up to 10 years
Population: All enrolled patients
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I (Chemotherapy) | Disease-free Survival | 42.9 months |
| Arm II (Chemotherapy, Bevacizumab) | Disease-free Survival | 40.6 months |
p-value: 0.9595% CI: [0.86, 1.15]Regression, Cox
Other Pre-specified
Perform Analyses of Tissue and Blood to Establish Factors That Predict for Clinical Outcome in Patients Receiving Chemotherapy, With or Without Bevacizumab, for Resected Early Stage NSCLC.
Time frame: From registration to death, up to 10 years
Population: Data for these studies were not collected
Other Pre-specified
To Determine Whether Smoking Status is Linked to Outcome for Patients With Resected Stage IB - IIIA NSCLC Treated With Chemotherapy With or Without Bevacizumab in the Adjuvant Setting.
Time frame: From registration to death, up to 10 years
Population: Data were not collected
Other Pre-specified
Toxicity Rates as Assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0
If the difference in the rate of a particular category of toxicities between the 2 arms (N=750 per arm) is at least 5% (4% vs. 9%), 96% power can be attained assuming a significance level of 5% (two-sided Chi Square test) and that the lower toxicity rate for one arm is 4%. A difference in the rates of grade 3-5 arterial thromboembolic events and bleeding events will be monitored and assessed between the treatment arms.
Time frame: Up to 1 year post-treatment